This invention relates to A-seco steroids. The compounds are also useful in preventing and treating neovascularization and may also be used to control ocular hypertension. Specifically, the invention is directed to A-seco steroids, pharmaceutical compositions comprising the A-seco steroids, and methods of treatment which comprise administering these compositions to treat ocular hypertension, including controlling ocular hypertension associated with primary open angle glaucoma, and to treat neovascularization. In addition, the compounds can be used in combination with glucocorticoids to treat ocular inflammation without the significant intraocular pressure rise commonly associated with the use of glucocorticoids.
Steroids functioning to inhibit angiogenesis in the presence of heparin or specific heparin fragments are disclosed in Crum, et al., A New Class of Steroids Inhibits Angiogenesis in the Presence of Heparin or a Heparin Fragment, Science, Vol. 230, pp. 1375-1378 (Dec. 20, 1985). The authors refer to such steroids as "angiostatic" steroids. Included within the new class of steroids found to be angiostatic are the dihydro and tetrahydro metabolites of cortisol and cortexolone. In a follow-up study directed to testing a hypothesis as to the mechanism by which the steroids inhibit angiogenesis, it was shown that heparin/angiostatic steroid compositions cause dissolution of the basement membrane scaffolding to which anchorage dependent endothelia are attached resulting in capillary involution; see, Ingber, et al., A Possible Mechanism for Inhibition of Angiogenesis by Angiostatic Steroids: Induction of Capillary Basement Membrane Dissolution, Endocrinology, Vol. 119, pages 1768-1775 (1986). More recently, other theories regarding the mechanism of action of angiostatic steroids have developed. For example, angiostatic steroid induced inhibition of neovascularization may occur due to: inhibition of vascular endothelial cell proliferation, Cariou, et al., Inhibition of Human Endothelial Cell Proliferation by Heparin and Steroids, Cell Biology International Reports, Vol. 12, No. 12, pp. 1037-1047 (December, 1988); or inhibition of vascular endothelial cell plasminogen activator activity, Ashino-Fuse, et al., Medroxyprogesterone Acetate, An Anti-Cancer and Anti-Angiogenic Steroid, Inhibits the Plasminogen Activator in Bovine Endothelial Cells, Int. J. Cancer, 44, pp. 859-864 (1989).
A group of tetrahydro steroids useful in inhibiting angiogenesis is disclosed in International Patent Application No. PCT/US86/02189, Aristoff, et al., (The Upjohn Company). The compounds are disclosed for use in treating head trauma, spinal trauma, septic or traumatic shock, stroke and hemorrhage shock. In addition, the patent application discusses the utility of these compounds in embryo implantation and in the treatment of cancer, arthritis and arteriosclerosis. Some of the steroids disclosed in Aristoff et al. are disclosed in U.S. Pat. No. 4,771,042 in combination with heparin or a heparin fragment for inhibiting angiogenesis in a warm blooded animal.
Compositions of hydrocortisone, "tetrahydrocortisol-S," and U-72,745G, each in combination with a beta cyclodextrin, have been shown to inhibit corneal neovascularization: Li, et al., Angiostatic Steroids Potentiated by Sulphated Cyclodextrin Inhibit Corneal Neovascularization, Investigative Ophthalmology and Visual Science, Vol. 32, No. 11, pp. 2898-2905 (October, 1991). The steroids alone reduce neovascularization somewhat but are not effective alone in effecting regression of neovascularization.
Tetrahydrocortisol (THF) has been disclosed for its use in lowering the intraocular pressure ("IOP") of rabbits made hypertensive with dexamethasone alone, or with dexamethasone/5-beta-dihydrocortisol; see Southren, et al., Intraocular Hypotensive Effect of a Topically Applied Cortisol Metabolite: 3-alpha, 5-beta-tetrahydrocortisol, Investigative Ophthalmology and Visual Science, Vol. 28 (May, 1987). The authors suggest THF may be useful as an antiglaucoma agent. In U.S. Pat. No. 4,863,912, issued to Southren et al. on Sep. 5, 1989, pharmaceutical compositions containing THF and a method for using these compositions to control intraocular pressure are disclosed. THF has been disclosed as an angiostatic steroid in Folkman, et al., Angiostatic Steroids, Ann. Surg., Vol. 206, No. 3 (1987) wherein it is suggested angiostatic steroids may have potential use for diseases dominated by abnormal neovascularization, including diabetic retinopathy, neovascular glaucoma and retrolental fibroplasia.
Many compounds classified as glucocorticoids, such as dexamethasone and prednisolone, are very effective in the treatment of inflammed tissues; however, when these compounds are administered systemically or topically applied to the eye to treat ocular inflammation, certain patients experience elevated intraocular pressure. Patients who experience these elevations when treated with glucocorticoids are generally referred to as "steroid responders." These pressure elevations are of particular concern to patients who already suffer from elevated intraocular pressures, such as glaucoma patients. In addition, there is always a risk that the use of glucocorticoids in patients having normal intraocular pressures will cause pressure rises great enough to damage ocular tissues. Since glucocorticoid therapy is frequently long term (i.e., several days or more), there is potential for significant damage to ocular tissue as a result of prolonged elevations in intraocular pressure attributable to that therapy.
The following articles may be referenced for further background information concerning the well-recognized association between ophthalmic glucocorticoid therapy and elevations in intraocular pressure:
Kitazawa, Increased Intraocular Pressure Induced by Corticosteroids, Am. J. Ophthal., Vol. 82, pp. 492-493 (1976); PA0 Cantrill, et al., Comparison of In Vitro Potency of Corticosteroids with Ability to Raise Intraocular Pressure, Am. J. Ophthal., Vol. 79, pp. 1012-1016 (1975); PA0 Mindel, et al., Comparative Ocular Pressure Elevation by Medrysone, Fluorometholone, and Dexamethasone Phosphate, Arch. Ophthal., Vol. 98, pp. 1577-1578 (1980); and PA0 Clark, Steroids, Ocular Hypertension and Glaucoma, J. Glaucoma, Vol. 4, pp. 354-369 (1995). PA0 R2 is H, OH, OC(.dbd.O)R.sub.7, CH.sub.3, CH.sub.2 CH.sub.3, C.tbd.CH, or R.sub.2 is combined with R.sub.3 to form a cyclic acetonide; PA0 R.sub.3 is H, CH.sub.3, OH, OC(.dbd.O)R.sub.7, or R.sub.3 may be combined with R.sub.2 to form a cyclic acetonide; PA0 R.sub.4 is H or CH.sub.3, with the proviso that if R4is CH.sub.3 then R.sub.3 is H; PA0 R.sub.5 is H, F or CH.sub.3 ; PA0 R.sub.6 is H, C(.dbd.O)R.sub.7, P(.dbd.O)(OH).sub.2 or a salt thereof; PA0 R.sub.7 is C.sub.1 to C.sub.8 alkyl, branched alkyl, cycloalkyl, or haloalkyl; PA0 R.sub.8 is (.dbd.O), OH or OC(.dbd.O)R.sub.7 and may be in the .alpha. or .beta. configuration, or R.sub.8 may be combined with R.sub.9 to form a lactone; PA0 R.sub.9 is C.tbd.CH, C(.dbd.O)CH.sub.3, COOH, COOR.sub.7, CH.sub.2 OH, CH.sub.2 OC(.dbd.O)R.sub.7, CONH.sub.2, CONHR.sub.7, CONR.sub.7 R.sub.7, or R.sub.9 may be combined with R.sub.8 to form a lactone; PA0 R.sub.10 is H, (.dbd.O) or OH, or OC(.dbd.O)R.sub.7 which may be in the .alpha. or .beta. configuration, or may be combined with R.sub.11 to form a double bond; and PA0 R.sub.11 is H, Cl, F, or may be combined with R.sub.10 to form a double bond. PA0 R.sub.1 is C(.dbd.O)CH.sub.2 OR.sub.6 ; PA0 R.sub.2 is OH; PA0 R.sub.3 is H; PA0 R.sub.4 is H; PA0 R.sub.5 is H; PA0 R.sub.6 is C(.dbd.O)R.sub.7 ; PA0 R.sub.7 is CH.sub.3 ; PA0 R.sub.8 is (.dbd.O); PA0 R.sub.9 is COOR.sub.7 ; PA0 R.sub.10 is OH and in the .beta. configuration or with R.sub.11 forms a double bond; and PA0 R.sub.11 is H, or combined with R.sub.10 forms a double bond.
Commonly assigned U.S. Pat. No. 4,945,089 discloses the use of the angiostatic steroid tetrahydrocortexolone in combination with a glucocorticoid to treat ocular inflammation without the intraocular pressure elevating effect commonly associated with topical administration of glucocorticoids. In addition, commonly assigned International Publication No. WO 91/03245 discloses the angiostatic steroids of Aristoff, et al. in combination with glucocorticoids to treat ocular inflammation without significant increase in intraocular pressure.